In a previous column, I discussed some of the techniques that have come along to make it simpler for contract labs, manufacturers and generic houses to keep up with “the rich kids.” In other words, it has become far easier today for a smaller company to mimic the R&D and process streams of the larger Pharma houses.

Modern instruments needed for process control—PAT, QbD, and QRM—were formerly well beyond the grasp of small contract and generic companies because of their high cost. Nowadays, both in terms of initial and ongoing costs and expertise in operating, newer introductions are both less expensive and simpler to operate properly and maintain.

Aside from Near-Infrared and Raman, I previously mentioned LIBS (LASER-induced breakdown spectroscopy) and two-dimensional NMR. Now, I felt that there were a few less obvious but well-publicized techniques worth suggesting for a modern process/R&D company.

X-ray Fluorescence
Not a technique that is included in traditional pharmaceutical curricula, however, with the advent of hand-held units, it should become more common than it is now. Where the range of materials open to this technique may be limited to mostly metals, it helps on several fronts.

1. Raw material inspection. Along with Raman or NIRS, XRF may also be used for RMID. With a worldwide supply chain, there are both accidental and deliberate instances of wrong materials being sent. In the case of lubricants, the most common materials contain stearic acid and its anion stearate (as Mg and Ca salts). Organic-centric ID methods (Raman and NIRS) may well pass the incoming raw material as “valid” since the spectrum largely resembles stearic acid in all cases while possibly missing the metallic counter ion. XRF is a fast, non-destructive way to ascertain the correct material. In conjunction with either Raman or NIRS, it assures both the organic portion and the proper salt.
2. Supply chain integrity. Generic drugs may enter the supply chain from non-regulated sources. In these cases, the perpetrators may use the incorrect lubricant, which could be seen by XRF. As well as containing “incorrect” lubricant and/or metals in the coating, the correct amounts of proper materials of both may vary from branded units in less expensively made counterfeits. Using the XRF unit one can ascertain the amounts of silicon, magnesium, and calcium (showing talc and amount of same), sulfur and chlorine, if they are present in the API, and titanium and iron, contained in the coating.

A simple program, available from XRF suppliers, using Principal Components Analysis, can plot the selected elements from “good/real” drug products or raw materials and, using, for example, cluster analysis, show how close or distant any particular sample is from the mean of pre-approved materials. A fast, non-destructive method, allowing further rests (e.g., dissolution profile), XRF seems to have become more and more useful in CMO/Generic application.

Ion Mobility “Spectroscopy”
Not really spectroscopy, closer to mass spectrometry, but still a super technology. We see these units at every airport, used by TSA for monitoring baggage for illicit drugs and/or explosives. In short, the sample and its matrix are vaporized. Early models, still used in airports, use a heated plate to vaporize the sample while later models use a solvent injection system, similar to gas chromatography, to vaporize samples. The sample, as its gaseous molecules, passes through an ionizing source, then through a charged grating of the same chare as the molecules, causing them to be repelled along a tube.

Unlike a true mass spectrometer, which operates with a vacuum in the tube made by a very expensive pump, IMS operates with a mild “headwind” from atmospheric air. This resistance affects and impedes the charged molecules proportionally according to their mass. Since each molecule acquired the same charge, the charge/mass ratio affects the momentum with which they are propelled by the charged grid. The headwind further separates the different molecules such that, when they finally interact with the second charged plate at the end of the tube, the molecules are well-resolved by mass, generating a “chromatogram.”

Initially, it was used for cleaning validation of process equipment. Surfaces were swabbed with small pieces of cotton, wet with solvent and placed on the heating pad. Instead of sending these swabs to a lab and waiting days for a result, the process staff knows in seconds if the equipment either a) needs more cleaning or b) is ready to immediately use for another batch. This application, alone, makes the instrument worth owning for increased productivity. But, as they say on late-night TV commercials, “Wait, there’s more.”

The instrument, now equipped with a heated injection port for syringes, may be used as either a) lower resolution of complex samples before a true mass spectrometer or b) as a substitute for routine (RMID or QC) GC or HPLC analyses. What’s the difference between IMS and HPLC? How does 20 milliseconds versus 10 to 20 minutes per result sound? All one would need to do is purchase a unit—several are available—to perform the dosage form grinding, extraction, and filtering, prior to injection, and a process that took hours could now only take minutes. This longer time estimate is based on preparing HPLC standards, equilibrating the column, extracting the API from tablets or capsules—20 per lot x 20 flasks = ~ 2-3 liters HPLC grade solvent; then, sonicate and/or shake, bring to volume, filter, place into vials—and injecting both samples and standards. Then there are always repeats and evaluation of chromatograms, and so forth.

Even in a standard batch-type GMP process, IMS would increase throughput by a large factor. Equipment would be available for manufacturing sooner and results could be available sooner, usually within a few hours of completion of a lot.

TeraHertz Spectroscopy
Formerly known as “far-infrared,” it was, for many years, a novelty with only research applications—structure elucidation of crystals—and the instruments were large, slow, and, of course, expensive. However, several years ago, far-infrared was rebranded “TeraHertz” and new instruments, along with new applications, came on the market. While I am a natural cynic, my occupation requires me to be familiar with every technique on the market, so, I checked it out.

A number of applications have been touted: RMID, tablet coating analysis, and tablet coating control being the most successful, to date. As far as the first application, THz has not proven superior to Raman or NIRS, so, if this is your only application, it may not be worth the cost.

A stronger case may be made for THz as a tool for both R&D and control of coating precision and multi-layer tablets. This is an excellent method for development of coating parameters, OOS inspections, and process checks, in real time.

Observations
While few of you will run out this week and purchase the technologies highlighted in this column, it will give you some ideas for control and streamlining for future consideration for when your potential client asks, “Can you…?” And your answer may then be, “Yes, we can.”

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Emil W. Ciurczak
DoraMaxx Consulting

Emil W. Ciurczak has worked in the pharmaceutical industry since 1970 for companies that include Ciba-Geigy, Sandoz, Berlex, Merck, and Purdue Pharma, where he specialized in performing method development on most types of analytical equipment. In 1983, he introduced NIR spectroscopy to pharmaceutical applications, and is generally credited as one of the first to use process analytical technologies (PAT) in drug manufacturing and development.